Zearalenone intermediates and their preparation

ABSTRACT

d,1-zearaleneone and mono- and diethers thereof, compounds having anabolic, estrogenic and fertility control properties, are prepared by a total chemical synthesis. An aromatic ring component, a diether of 2-formyl-4,6-dihydroxy benzoic acid, is prepared by selective reduction of a diether of 3,5-dihydroxy phthalic anhydride; an aliphatic component, 2-loweralkoxy-6methyltetrahydropyran-2-butyl triphenyl phosphonium halide, is prepared via a sequence of reactions involving the condensation of 2-hydroxyhexanoic acid- delta - lactone with pent-4-enyl magnesium bromide, subsequent treatment with alcoholic acid to form 2-(pent-4-enyl)-2-loweralkoxy-6-methyl tetrahydropyran, which substance is in turn ozonized, reduced with alkali metal borohydride, reacted with an alkyl or aryl sulfonyl halide, and then with sodium bromide or iodide to afford 2-( delta halobutyl)-2-loweralkoxy-6-methyl tetrahydropyran, which latter substance is reacted with triaryl phosphine to afford the abovestated aliphatic component. The aromatic and aliphatic components are coupled and the resulting 1-(3,5-diether-6-carboxyphenyl)-10hydroxy-1-undecen-6-one ring-closed with trifluoroacetic anhydride to yield d,1-zearalenone diether, which is cleaved with boron tribromide or pyridine hydrochloride to d,1-zearaleneone.

United States Patent [72] Inventors Norman L. Wendler 54] ZEARALENONEINTERMEDIATES AND THEIR PREPARATION 5 Claims, No Drawings [52] US. Cl260/521, 260/240, 260/333, 260/3432, 260/3435,

[5 l] Int. Cl C071: 65/02 [50] Field 0! Search 260/473, 474, 520, 52]

[56] Relerences Cited UNITED STATES PATENTS 3,023,183 2/1962 Nelson260/474 OTHER REFERENCES Wagner et al., Synthetic Organic Chemistry,Wiley, New York(l953) PP-4l7,485.

Primary Examiner.lames A. Patten Attorneys-J. Jerome Behan, l. LouisWolk and John Frederick Gerkens ABSTRACT: d,l-zearaleneone and monoanddiethers thereof, compounds having anabolic, estrogenic and fertilitycontrol properties, are prepared by a total chemical synthesis. Anaromatic ring component, a diether of 2-formyl-4,6- dihydroxy benzoicacid, is prepared by selective reduction of a diether of 3,5-ciihydroxyphthalic anhydride; an aliphatic component,2-loweralkoxy-6-methyltetrahydropyran-Z-butyl triphenyl phosphoniumhalide, is prepared via a sequence of reactions involving thecondensation of 2-hydroxyhexanoic acid-6- lactone with pent-4-enylmagnesium bromide, subsequent treatment with alcoholic acid to form2-(pent-4- enyl)-2-loweralkoxy-6-methyl tetrahydropyran, which substanceis in turn ozonized, reduced with alkali metal borohydride, reacted withan alkyl or aryl sulfonyl halide, and then with sodium bromide or iodideto afford 2-(6-halobutyl)- 2-loweralkoxy-6-methyl tetrahydropyran, whichlatter substance is reacted with triaryl phosphine to afford theabovestated aliphatic component. The aromatic and aliphatic componentsare coupled and the resulting l(3,5-diether6-carboxyphenyl l O-hydroxyl-undecen-6-one ring-closed with trifluoroacetic anhydride to yieldd,l-zearalenone diether, which is cleaved with boron tribromide orpyridine hydrochloride to d, i-zearaleneone.

ZEARALENONE INTERMEDIATES AND THEIR PREPARATION BACKGROUND OF THEINVENTION The optically active form of 6-(l-hydroxy-6-oxo-trans-lundecenyl-B- resorcylic acid-p-lactone has beenprepared by fermentation as described in US. Pat. No. 3,196,019, andthis substance is now known as zearalenone. It has the structuralformula:

l-leretofore it has been obtainable only via fermentation. It. is thepurpose of this invention to provide for the first time a total chemicalsynthesis of d,l-zearalenone as well as of certain monoand diethersthereof.

SUMMARY This invention relates to the novel compound d,lzearalenone. Itrelates further to m0noand diethers thereof, and to the total chemicalsynthesis of these materials by a process that comprises elaboration ofthe aromatic ring component of d,l-zearalenone diether, elaboration ofan appropriate aliphatic component, and finally coupling of these twosubstances followed by ring closure of the acid produced on saidcoupling. The invention also relates to the novel compounds obtained anduseful as intermediates in this total synthesis, and to processes formaking such intermediates. d,l-zearalenone, and the ethers thereof,described hereinafter are valuable compounds in that they possess theanabolic and estrogenic activity and also the fertility controlproperties of zearalenone produced by fermentation. They are also usefulas intermediates in making other compounds having such biologicalactivity, as for example by reduction of the aliphatic double bondand/or the carbonyl moiety of d,l-zearalenone. Formation of suchsubstances from fermentation-derived zearalenone has been described inthe art.

The overall process which we have employed for the total chemicalsynthesis of d,l-zearalenone may be pictured structurally as follows:

Aromatic Component 0R f OR I c CO0H O RIO R10 CHO i (l 1 ()ll COOR,

11,0 CHO Ia Aliphatic Component (3H2 CH;CO(CH=):COOH -t IIIa 1O (1H3(3H3 Mi] M 4m. Iv III l CH3 (IT/H3 I Y B a V VI v KB 0 2 C1H1S OjOHflCM/R1 OR; VIII VII (III;

/\A OR x- IX Coupling ()II; ()It l l COONa IX 3 A R 0 CH0 map m IXa a ICODE R10 \G%C O OR fl) OH; OH I(I) CH1 1 C C\O XI XIII OH fl) CH C Inthe above flowsheet the symbols R and R represent benzyl, a straightchain loweralkyl radical such as methyl, ethyl, n-propyl or butyl,methoxymethyl or tetrahydropyranyl; R represents a loweralkyl radicalexamples of which are methyl, ethyl, propyl, butyl and isopropyl; Rrepresents loweralkyl, examples being methyl, ethyl, or propyl; Xrepresents bromo or iodo and Y represents aryl such as phenyl, tolyl,and the like, or loweralkoxy such as methyl, ethyl or butyl.

Aromatic Component ln accordance with the first stage of our process,2-formyl- 4,6-dialkoxy benzoic acid, 2-formyl-4,6-dibenzyloxy benzoicacid, 2-formyl-4,6-ditetrahydropyranyloxy or 2-formyl-4,6-dimethoxymethoxy benzoic acid (I) is produced by the selective reductionof the corresponding diether of 3,5-dihydroxy phthalic anhydride. Forthis conversion of the phthalic anhydride to the substituted benzoicacid we employ as reducing agent either a deactivated lithium aluminumhydride such as an alkoxy lithium aluminum hydride, or catalytichydrogenation with platinum oxide catalyst. It is preferred to use thealkoxy aluminum hydride, examples of which are lithium tri-tbutoxyaluminum hydride, lithium tri-isopropoxy aluminum hydride or lithiumtri-sec-amyloxy aluminum hydride. The process is brought about underanhydrous conditions in a solvent such as tetrahydrofuran, ether,dixoane or mixtures of tetrahydrofuran-benzene. Alcoholic solventsshould be avoided. For best results it is desirable to carry out theprocess by adding one equivalent of the reducing agent to the2,4-disubstituted phthalic anhydride at temperatures of from about 5 toC. The reaction mixture may then be warmed to room temperature orslightly above and the desired ether of 2- formyl-4,6-dihydroxy benzoicacid (I) recovered by extraction techniques known to those skilled inthis art.

The catalytic reduction process using platinum catalyst is brought aboutin a neutral solvent such as ethyl acetate until the desired amount ofhydrogen is consumed. This may be carried out at room temperature forperiods of time from about 5 to 20 hours.

It is preferred to prepare as this intermediate in our process2-formyl-4,6-dimethoxy benzoic acid, although other diethers such as thediethyl, dipropyl, dibenzyl, di-tetrahydropyranyl or dimethoxymethylethers may be used if desired. Certain of the diethers of 3,5-dihydroxyphthalic anhydride used as starting materials in this process are known;those that are not specifically described in the prior art are made bysimilar processes using the appropriate etherifying agent.

The 2-formyl-4,6-disubstituted benzoic acid of formula 1 above may beesterified by treatment with a diazoloweralkane such as diazomethane ordiazoethane. This is brought about by passing the diazoalkane through asolution of the 2-formyl- 4-OR,-6-OR-benzoic acid (where R and R are aspreviously defined) in a suitably inert solvent such as tetrahydrofuranor dioxane. Excess diazomethane is removed and the desired esterobtained by evaporation of the reaction solvent. Aliphatic ComponentAccording to this 553% of our invention, 2-loweralkyl-6-methyl-tetrahydropyran-2-butyl-triaryl (or trialkoxy) phosphoniumbromide or iodide (IX) is produced via a sequence of reactions beginningwith the known 4-acetyl butyric acid. In the first step of thissequence, 4-acetyl butyric acid is treated with alkali metal borohydrideand then with mineral acid to afford 2hydroxyhexanoic acid-B-lactone(ll). The alkali metal borohydride reaction is brought about in thepresence of a weak base such as an alkali metal bicarbonate at aboutroom temperature for from 1 to 6 hours. The mixture is then made acidicwith a mineral acid, e.g., a hydrohalic acid, in order to form thecyclic lactone. It will be appreciated by those skilled in this art thatthis lactone is a racemate and, therefore, that the ensuingintermediates in out total synthesis will exist in the opticallyinactive d,l form.

In the next step of our process, the 2-hydroxy hexanoic acid-8-lacton isreacted with the Grignard reagent pent-4-enyl magnesium bromide toafford 2-( pent-4-enyl)-6-methyl-A"'- dihydropyran (III). In order toachieve optimum results in this reaction, we employ essentiallyequimolar amounts of the hexanoic acid lactone and the Grignard reagent,and effect the reaction by adding the Grignard reagent to the lactone.The immediate reaction product is primarily the open-chain compoundIO-hydroxy-l-undecen-6-one (llla) which is converted without isolationto the desired cyclic compound III by distillation in vacuo. It isdesirable that a trace amount of acid be present during the distillationas a catalyst and it has been found that the acidity of ammoniumchloride is sufficient for this purpose.

The dihydropyran Ill is next converted to 2-(pent-4-enyl)-2-loweralkoxy-6-methyl tetrahydropyran (IV) by treatment with aloweralkanol in the presence of acid. lt will be appreciated that thealkoxy group at the 2-position corresponds to the particular alkanolemployed in the process. It is preferred to use methanol with consequentformation of the 2-methoxy tetrahydropyran (lV where R representsmethyl). lnasmuch as the methoxy compound is a preferred embodiment ofthe invention and for the sake of convenience, reference will frequentlybe made in the ensuing description to the 2- methoxy tetrahydropyrancompounds, but it should be understood that this is not to be construedas a limitation of the invention which includes within its scope other2-loweralkoxy tetrahydropyran compounds. The particular acid necessaryfor the preparation of compound IV is not critical and may be anonoxidizing mineral acid such as hydrochloric, sulfuric, or p-toluenesulfonic acid. Hydrochloric acid is preferred. The reaction is carriedout at about room temperature for from 1 to 6 hours under essentiallyanhydrous conditions and the desired product then recovered from thereaction mixture by known methods. When primary alcohols such asethanol, npropanol or butanol are utilized in place of methanol, thecorresponding 2-ethoxy, 2-n-propoxy and Z-butoxy compounds of formula IVare produced.

The olefin obtained as described immediately above is next converted to2-loweralkoxy-6'methyl tetrahydropyran-Z-butyraldehyde (V) by reactionwith ozone and decomposition of the resulting ozonide. The ozonizationis brought about in the cold, i.e. at temperatures of about to 30 C.using an excess of ozone. When the reaction is complete, the aldehyde Vmay be recovered by decomposing the ozonide with a mild reducing agentsuch as dimethyl sulfide or a palladium catalyst, and isolating theproduct by known techniques. Representative compounds which may beprepared in this fashion are 2-methoxy- (or 2-ethoxy, 2-n-propoxy, or2-butoxy) 6-methyl-tetrahydropyran-2-butyraldehyde, (V).

When the aldehyde is to be used directly in the next step of ourprocess, it is unnecessary to isolate or purify it, and in fact it is apreferred embodiment of the invention to treat the aforementionedozonide directly with an alkali metal borohydride such as sodiumborohydride in a loweralkanolic solvent to produce the carbinol2-(6-hydroxybutyl)-2-loweralkoxy-6-methyl tetrahydropyran (VI). Theborohydride reduction, in which the ozonide is decomposed and thealdehyde reduced, is preferably initiated in the cold and carried out attemperatures of about 20-40 C. for from A to 3 hours. The solvent isthen removed and the desired product isolated from the residue bystandard extraction techniques. The reduction of the aldehyde (V) to thecarbinol Vl may also be brought about with other reducing agents such aslithium aluminum hydride in an ethereal solvent, or by catalytichydrogenation in a neutral solvent using a platinum catalyst. In thismanner there is produced 2-(S-hydroxybutyl)-2-methoxy-(or Z-ethoxy or2-propoxy) o-methyl-tetrahydropyran (VI).

In carrying out the above reduction, it is desirable to main tain thereaction mixture free of aqueous acid to assure maximum formation of thecarbinol VI. In the presence of aqueous acid the sprio compound1,7-di-oxa-2-methyl spiro [5:51-undecane (Via) is produced in preferenceto the open chain carbinol:

VIE

This substance is also obtained'by treatment of2-(8-hydroxybutyl)-2-loweralkoxy-6-methyl tetrahydropyran VI withaqueous alcoholic mineral acid such as aqueous methanolic hydrochloricacid. The spiro compound may also serve as an intermediate in ourprocess since it is transformed to the carbinol Vl by treatment with dryalcoholic hydrogen halide such as anhydrous methanolic hydrogenchloride.

The carbinol VI is next reacted with an appropriate alkyl or arylsulfonyl halide in the presence of an acid binding agent to produce2-(8-aryl or alkyl sulfonyloxy)-2-loweralkoxy-6- methyl tetrahydropyran(VII). It is preferred to utilize ptoluene sulfonyl chloride as the.reagent in this step of our process thereby forming the p-toluenesulfonyloxy derivative, but other alkyl and aryl sulfonyl halides suchas methane sulfonyl chloride, ethane sulfonyl chloride and benzenesulfonyl chloride may be used if desired. It is also convenient andpreferred to bring the reaction about in a basic solvent such aspyridine or one of the picolines which also serves as an acid bindingagent. The reaction is initiated at temperatures of about 0-l0 C. andallowed to proceed in the cold for from 4-20 hours. Examples ofcompounds obtained in this way are2-(8-p-toluenesulfonyloxy)-2-methoxy-6-methyl tetrahydropyran,2-(6-benzenesulfonyloxy)-2-ethoxy-6- methyl tetrhydropyran, and2-(6-methanesulfonyloxy)-2-npropoxy-o-methyl tetrahydropyran.

The tetrahydropyran VII obtained as described above is occasionallyfound to contain small amounts of the enol ether and hydroxy ketoneforms of the product. These are reconverted to the tetrahydropyran formby mild treatment with dilute anhydrous alcoholic mineral acid. It isconvenient and preferred to employ dilute methanolic hydrogen chloridefor this purpose when the 2-loweralkoxy substituent is methoxy.

It should be noted at this point that the novel tetrahydropyrans of ourinvention are susceptible during reaction to ring opening, but that theyare readily reconverted to the desired tetrahydropyran form withanhydrous loweralkanolic hydrogen halide. The alcohol should be the onecorresponding to the loweralkoxy substituent of the tetrahydropyran inorder to preclude formation of mixtures and/or complete interchange ofthe alkyl moiety of the alcohol and the alkyl moiety R As the hydrogenhalide, it is preferred to use hydrogen chloride, although in thosecases where the tetrahydropyran contains a halogen, such as in compoundVIII, the corresponding hydrogen halide is employed.

According to the next step of our total chemical synthesis ofd,l-zearalenone, the sulfonyloxy compound VII is reacted with an alkalimetal bromide or iodide to afford the 2-(8-bromobutyl)-2-loweralkoxy-6-methyl tetrahydropyran or 2- (aiodobutyl)-2-loweralkoxy-6-methyl tetrahydropyran (VIII). This reactionis carried out by heating the tetrahydropyran VII with an alkali metalhalide in'a loweralkanol for from 2 to 10' hours, using temperatures offrom about 50-l25 C. It is preferred to employ sodium bromide inmethanol as solvent. Upon completion of the reaction and removal of thesolvent, the oil thus obtained is'treated briefly with loweralkanolichydrogen bromide in order to insure that all of the product is in thetetrahydropyran form. Examples of compounds obtained in this way are2-('8-bromobutyl)-2- methoxy-6-methyl tetrahydropyran,2-(6-bromobutyl)-2- ethoxy-6-rnethyl tetrahydropyran, and2-(8-iodobutyl)-2-npropoxy-G-methyl tetrahydropyran.

The final reaction for elaborating the aliphatic component for our totalsynthesis comprises formation of 2-loweralkoxy- 6-methyltetrahydropyran-2-butyl triaryl phosphonium halide or2-loweralkoxy-6-methyl-tetrahydropyran-Z-butyl-trialkoxy phosphoniumhaIide'(IX) by the reaction of compound Vlll with a triaryl or trialkoxyphosphine in a suitable solvent at temperatures of between about 50 and100 C. It is convenient to employ a loweralkanol such as methanol orethanol for this reaction. Although triphenyl phosphine is preferred,other triaryl phosphines and trialkoxy phosphines such as triethoxyphosphine and trimethoxy phosphine may be utilized as well. At the endof the reaction the volume of the reaction mixture is reduced and thephosphonium salt precipitated with benzene or toluene. The product maycontain a minor amount of the open-ring hydroxy ketone form and, whenthis occurs, it

v is conveniently reconverted to the desired tetrahydropyran fon'n (IX)by treatment with dilute alkanolic hydrogen halide, and preferablydilute methanolic hydrogen bromide. When the starting material for thisreaction is an iodobutyl tetrahydropyran, -the resulting phosphoniumsalt will, of course, be an iodide. Representative examples of theseintermediates are 2-methoxy-6-methyl-tetrahydropyran-2-butyl triphenylphosphonium bromide, 2-ethoxy-6-methyltetrahydropyran-2-butyl triphenylphosphonium iodide, and 2-n-propoxy-6-methyl-tetrahydropyran-2-butyltriethoxy phosphonium bromide. Compound IX is considered as thealiphatic component of our total synthesis and it is this substancewhich is reacted with the substituted benzoic acid I in the finalsequence of reactions leading to d,l-zearalenone (X- ll). CondensationIn the final step of our' total synthesis the 2-loweralkoxy-6- methyltetrahydropyran2-butyl triaryl (or trialkoxy) phosphonium halide(compound IX) is first treated with methyl sulfinyl carbanion (generatedfrom dimethylsulfoxide and alkali metal hydride) in order to form thecorresponding phosphorane. This substance is also sometimes referred toas the ylid. This phosphorane in solution is reacted with an alkalimetal salt of 2-formyl-4-OR,-6-OR benzoic acid (where R and R, are aspreviously defined). The immediate reaction product is an alkali metalsalt of 2-[8-(2-carboxy-3-OR-5-OR -benzylidene)]butyl-2-loweralkoxy-6-methyl tetrahydropyran of formula Xa:

to form the cis and/or trans geometrical isomers because of T o astw'ed, cooled SOTifiiOH of 4.16 g. of 2,4-dimethoxthe aliphatic doublebond, our process affords predominantly yphthalic anhydride in 60 ml. ofanhydrous tetrahydrofuran at the desired transisomer. Compound X isconveniently referred 10 C. there is added over 30 minutes a solution of5.10 g. of to as the seco acid derived from zearalenone diether.Examlithium tri t-butoxy aluminum hydride in 60 ml. of ples of the ethersubstituents which may be present in comtetrahydrofuran. The coolingbath is removed and the mixture pound X are methoxy, ethoxy,methoxymethoxy, and is stirred for 18 hours at room temperature. Themixture is tetrahydropyranyloxy. This acid (X) i als o in f then cooledto 10-15 C. and ml. of saturated aqueous zearalenone dimethyl ether byreaction of the latter comsodium sulfate is added over a 5-minuteperiod. Dilute pound with alkali metal hydroxide in he pres n f dimethyhydrochloric acid is added and the mixture is extracted with sulfoxide,the reaction being carried out at about 75l50 C. 10 ethyl acetate. Theethyl acetate extracts are combined, dried for from I to 3 hours. d, 1-Sec. acid is obtained in this process over magnesium sulfate andconcentrated to dryness to yield a even in t o Cases Where h Startingmaterial is Optically semicrystalline residue. Crystallization of theresidue from pure. acetoneether yields 2-formyl-4,6-dimethoxybenzoicacid,

The loweralkyl esters of the seco acid (X) are prepared by 193 196 creaction of the free acid with an excess of diazoloweralkane i52-fonny|-4,6 diethoxybenzoic acid and 2-f |-4 6- for about l5 o 60minutes at about room temperature- The dibenzyloxybenzoic acid areobtained by repeating the above resulting ester is then isolated byremoval of the solvent and experiment ith 2,4-diethoxy or 24-dibenzyloxyphthalic anexcess diazolakane, and purified by knowntechniques. h d id In accordance with the next step of our invention,the The 2,4 dimethoxyphtba1ic anhydride used as starting diether ofdJ-ZeaI'aIOHOHe is P p y "eating the material in this experiment is aknown compound. Other 2,4- 5690 acid with a gg agent Such asti'ifliioi'oacetih di-loweralkoxyphthalic anhydrides, such as the2,4-diethoxy anhydride or dicyclohexylcarbodiimide. Trifluoroaceticanand dbmbroboxy etbers, d z di lk h h li hydride is the preferredreagent and with it the desired converhydrides such as the2,4;dibenzybXy ether are made in of compound X to compound xi is broughtaboui in the similar fashion as the 2,4-dimethyl ether with theappropriate cold in a suitable solvent such as benzene, toluene orxylene. th -if i agent Alternatively, they may be Obained by Uponcompletion of the reaction, which hoih'ia-iiy takes from cleaving thedimethyl ether with acid to 2,4-dihydroxyphthalic about A to 3 hours,the mixture is made basic and the desired anbydride and h if i by knownmethods d,l-zearalenone diether conveniently extracted into a non- B, 24 i i i polar solvent such as benzene or toluene, and recovered and 4,6Dimetboxyphthalic anhydride 325 mg) is Purified therefrom by knownchemical techhiqiihsih this hydrogenated at 257 C. under 50 psi. ofpressure in 170 ml. of gard, it has been found quite satisfactory toachieve the final h l t employing 278 mg. of platinum oxide asPurification by chromaiogi'aphy an adsorbent such as silica catalyst,for 18 hours. The catalyst is removed by filtration and g or aiumihathismanner there are Prepaied compounds the filtrate is concentrated invacuo to a solid residue. The Such as dJ'Zeai'aiehiihe dimethyi etherdizearaienone residue is extracted with benzene, filtered and thebenzene diethyl ether, dvi'zeai'aiehohe dibehzyi ether d'izcai'aienonesolution diluted with ethyl acetate until the solvent ratio isdimethoxymeihyi ether ahd d'izeai'aiehone about 1:1, and then extractedwith 5 percent aqueous sodium diieh'ahydi'pyi'ahyieihei'- bicarbonatesolutiomThe alkaline solution is then acidified The fihai p in oursynthesis ofdti'zeai'aienom Sen-is 40 with 2.5 N hydrochloric acid andextracted with chloroform. complished by cleaving the diether (Xl) withboron tribro- The organic phase is washed with water dried over magnesimide alternatively with Pyridine hydrochionde' The boron um sulfate andconcentrated in vacuo to give pure crystalline tribromide reaction is arapid one and the ether cleavage is 240m,y| 46 dimetboxybenzbic acidsubstantially complete in a matter of minutes at temperatures Methyl 2Fonny| 4,bDimehowbenzoate of from about 10 C. to about +15 C. Removal ofthe sol- Diazomethane is generated by h procedure f [3 3 Vent affordsCrude P which may be Purified either [Rec Trav. Chim 73 229 (1954)] andunder a gentle stream directly y crystaiiizaiioh from a Solvent such asof nitrogen excess diazomethane is passed into a solution ofnitl'omeihahev Or y chromatography on?!" adsorbent such as 400 mg. of2-formyl-4,6-dimethoxybenzoic acid in 10 ml. of silica gel, foiiowed yci'ystaiiizatioh from a suiiabii? Organic tetrahydrofuran. After 30minutes the excess diazomethane olv n and solvent are removed undervacuum. The crystalline when Py hydi'ochioi'ide is employed as the etherresidue is crystallized from acetone-ether to give pure methyl cleavingagent, the reaction is carried out at elevated tempera- 2-f r l..4 6 diethoxyb nzoate 85 37 (1 IUI'CS Of about 125 -200 and the resultingproduct exother lower alkyl esters uch as [he ethyl, n-p opyl andtracted and purified in the Same m nn r as described butyl esters areobtained by treating 2-formyl-4,6-dimethoxmediately a oveybenzoic acidwith the appropriate diazoalkane using the our invention also Provides amethod for synthesizing the above procedure. Similarly, methyl 2-formyl4,6-dibenzyloxmonoethers of d,l-zearalenone by selective cleavage of theybenzoate and ethyl 2.f l-4 6-di th b z t are diether (XI). This iseffected with either boron tribromide or d d b reaction f 2.f 4 6 dib bi boron trichloride. The cleavage of the ether radical at the 2-I acid idiazomethane and reaction f 2.f 4 6 di th position is essentiallyinstantaneous and when production of ybenzoic acid with diazoethane. the4-monoether is desired, the d,l-zearalenone diether is, contacted onlymomentarily with the boron trihalide, i.e., for EXAMPLE 2 preferablyless than 1 minute. The monoether is isolated and 2 HydmXyhexanic Acid 6Lact0ne (n) purified in essentially the same way as described above forpu- To a stirred solution of 13014 (0.1 mole) of 4 acety|burify1ngd,l-zearalenone itself. t 80 l f t t lo 082 0 12 l A l 'ndi t d01 lzearalenone and the either ync m i o wa er For] ammg 0 mo 8) d B a:y f F e d X] X n a ofsodlum blcarbonate there 15 added protionwise at 0C. [.89 enva ives ereo compoun s a growth promotingactivity in animalsas well as estrogenic and E SZ ZZ g g gg i' 21 3; 2 :525 5 :32 emu-0pm:activity acidic with hydrochloride acid to pH 2. The mixture is allowedThe following exampies. glven for the purpose ofluustra' to stand for 19hours at room temperature, and then is satunon and not by way ofhmnauon'rated with sodium chloride and extracted with diethyl ether. The etherextract is washed twice with saturated sodium EXAMPLEI chloride solutionand dried over anhydrous sodium sulfate. A. 2-Formyl-4,6-Dimeth0xyben 0iAcid The ether solution is evaporated to a residue, and the residuedistilled in vacuo to afford 9.5 g. of 2-hydroxyhexanoic acid-8-lactone, b.p. ll2-113C./21 mm.

EXAMPLE 3 2-(pent-4-enyl)-6-Methyl-A -Dihydropyran (111) To a stirredsuspension of 7.296 g. (0.2968 mole) of activated magnesium in 40 ml. ofdry ether there is added a solution of 35.397 g. (0.2375 mole) ofl-bromo-4-pentene in 90 ml. of dry ether under an atmosphere ofnitrogen. This is accomplished by first adding a small amount of thebromo compound and heating the mixture to reflux in order to initiatethe reaction. The remaining amount of bromopentene is added at a ratesuch that the reaction mixture refluxes without an external source ofheat. After the addition is complete (1% hours), the reaction mixture isrefluxed for an additional 40 minutes and then cooled to roomtemperature. The 4-pentenyl magnesium bromide Grignard reagent thusprepared is added dropwise to a stirred solution of 27.108 g. (0.2375mole) of 2- hydroxyhexanoic acid-vS-lactone in 300 ml. of dry ether at15 C. over a 2-hour period and under an atmosphere of nitrogen. Theresulting heterogenous reaction mixture is stirred at 1 C. for 30minutes and then treated with a saturated aqueous solution of ammoniumchloride. The aqueous layer is extracted with ether. The ether solutionand extracts are combined and extracted with percent aqueous sodiumhydroxide in order to remove any unreacted lactone. The ether solutionis then washed successively with water, saturated ammonium chloride andsaturated sodium chloride. it is then dried over anhydrous sodiumsulfate, and the ether removed by evaporation in vacuo. The residue,which contains a large proportion of -hydroxy-l-undecen-fi-one, isdistilled in vacuo to afford 20.363 3. (51.5 percent) of 2-pent-4-enyl)-6-methyl-A -dihydropyran, b.p. 52-54 C./0.65 mm.

Brief treatment of 2(4'-pentenyl)-6-methyl-A- dihydropyran with aqueoushydrochloric acid affords the open chain compoundIO-hydroxy-l-undecen-6-one (111a), l.R.:' A 3.02. 5.88 ,u.. I V V Max.

EXAMPLE 4 2-( Pent-4-Enyl)-2-Methoxy-6-Methyl Tetrahydropyran (IV) 40ml. of 1 percent HCl-methanol solution reaction added, with stirring to15.3 g. of 2-(pent-4-enyl)-6-methyl-A dihydropyran at 0 C. With thefirst addition of about 1 ml. of 1 percent HC l-methanol the S-of thereaction mixture rises to about 50 C. It is cooled to 25 C. and the restof the methanolic hydrogen chloride is added at that temperature. Themixture is stirred for 3% hours, and then an excess of solid sodiumbicarbonate is added to it. It is stirred for minutes at roomtemperature and the reaction mixture then filtered to remove the solids.The filtrate is evaporated to a residue at 30 C. under vacuum. A smallvolume of ether is added, the mixture filtered, and the filtratedistilled in vacuo to give 2- (pent4-enyl)-2-methoxy-6-methyltetrahydropyran as a colorless oil, b.p. 57-l59 C./0.65 mm.

When ethanolic hydrogen chloride is employed in the above reaction inplace of methanolic hydrogen chloride, 2-(Pent-4- enyl)-2-methyltetrahydropyran is obtained.

EXAMPLE 5 2-Methoxy-6-methyl Tetrahydropyran-2-Butryaldehyde (V) Asolution of 9.915 g. of 2-(pent-4-enyl)-2-methoxy-6- methyltetrahydropyran in 100 ml. of dry methanol is treated with a steadystream of 3 percent ozone at 70 C. until the effluent gas turnsstarch-potassium iodide indicator blue. Addition of ozone is thenstopped and excess ozone removed by bubbling nitrogen through thereaction mixture. This mixture contains the ozonide of2-methoxy-6-methyl tetrahydropyran- Z-butry-aldehyde, which may be useddirectly without isolation or further purification in the next step ofthe process.

In order to isolate 2-methoxy6-methyl tetrahydropyran-2- butyraldehydethe following procedure is used: An excess of dimethylsulfide is addedat about 60 C. to the methanol solution of ozonide, and the mixtureallowed to warm to room temperature over 5-6 hours. The solvent is thenevaporated in vacuo and the residue extracted into ether. The ethersolution is washed with water, dried over sodium sulfate andconcentrated to dryness in vacuo to give 2-methoxy-6-methyltetrahydropyran- Z-butyraldehyde.

EXAMPLE 6 2-(8-Hydroxybutyl)-2-Methoxy-6-Methyl Tetrahydropyran (V1);l,7-Dioxa-2-methyl-Spiro[5:5 lundecane The methanolic solution ofozonide obtained as in example 5 is brought to about 20 C., and 9.45 g.of solid sodium borohydride is added slowly to it at a rate such thatthe temperature does not exceed 0 C. The mixture is then stirred forhour at 0 C. and for 1% hours at room temperature. Most of the methanolis then removed by distillation at about 40 C. under vacuum. Water isadded to the semisolid residue and the resulting mixture extracted withether. The ether extracts are combined, washed with water, dried overanhydrous sodium sulfate and finally evaporated to dryness to give9.13g. of 2-(8-hydroxybutyl)-2-methoxy-6-methyl tetrahydropyran as acolorless liquid T.R.: L'; 3.0m; n.m.r. (CDCl )83.46 '(s, 0 Cl), Whenthe above product is treated for l5minutes with dilute methanolichydrochloric acid, it is quantitatively transformed to1,7-dioxa-2-methyl-spiro [5:5]undecane. This latter substance isrecovered by concentrating to dryness, extracting the residue withether, washing the ether extract with sodium bicarbonate, filtering andfinally concentrating the ether solution to dryness.

EXAMPLE 7 2-(8-Toluenesulfonyloxy2Methoxy6-Methyl-Tetrahydropyran (V11)To a stirred solution of 8.526 g. of2-methoxy-2-(4'-hydroxybutyl)-6-methyl tetrahydropyran in 40 ml. of drypyridine there is added at 0 C. 16.205 g. of purified p-toluenesulfonylchloride under an atmosphere of nitrogen. The clear solution immediatelybecomes heterogenous due to the separation of pyridine hydrochloride.The reaction mixture is stirred for 17 hours at about 5 C. and thenpoured into an ice-water mixture containing 38.64 g. of sodiumbicarbonate. The mixture is stirred for 1% hours, then extracted withdiethyl ether. The ether extracts are combined, washed with 5 percentaqueous sodium carbonate, dried over anhdyrous sodium sulfate andevaporated to dryness at about 40 C. in vacuo. There is obtained aresidue containing 12.945 g. of2-(8-p-toluenesulfonyloxy)-2-methoxy-6-methyl tetrahydropyran; [.RJAQ'Q'6.27, 7.38 and 8.48 1

The product, obtained as described above, is sometimes accompanied byminor amounts of the enol ether and hydroxy ketone forms; the latter twoforms are converted to the tetrahydropyran form by treatment of theentire product with 1 percent methanolic hydrogen chloride.

EXAMPLE 8 2-(S-Bromobutyl)-2-Methoxy-6-methyl (VIII) A stirred solutionof 9.368 g. of 2-(8-p-toluene-sulfonyloxy2 -methoxy-6-methyltetrahydropyran and 55 ml. of dry methanol containing 6.761 g. of sodiumbromide is gently refluxed for 5 hours under an atmosphere of nitrogen.A fine precipitate of sodium bromide appears immediately after therefluxing is started; this redissolves in about 1 hours and thereaftercrystalline sodium p-toluene sulfonate appears. After 5 hours themixture is filtered and the filtrate concentrated in vacuo to dryness;the residue is dissolved in ether, filtered and evaporated to dryness toyield an oily material which is dissolved in 1 percent methanolichydrogen bromide. The methanol solution is neutralized with solid sodiumbicarbonate, concentrated to dryness in vacuo and the residue dissolvedin ether. The ethereal solution is filtered and the filtrate thenconcentrated to dryness. There are obtained 7.173 g. of

Tetrahydropyran tetrahydropyran;

and 3.l7(s,-OCH

EXAMPLE 9 2-Methoxy-6-Methyl Tetrahydropyran-Z-Butyl Triphenyl 10Phosphonium Bromide (IX) A mixture of 3.975g. of2-(S-bromobutyl)-2-methoxy-6- methyl tetrahydropyran, 4.338 g. oftriphenyl-phosphine and30 ml. of dry methanol is heated at reflux forhours under an atmosphere of nitrogen. At the end of this time most ofthe methanol is removed by evaporation of 40 C. under. vacuum. To theresulting residue there is added dry benzene to precipitate the desiredphosphonium salt. The benzene layer is decanted, and the residue washedwith fresh benzene. The residue is then concentrated to a light yellowfoam containing predominantly 2-methoxy-6-methyl tetrahydropyran-2-butyl triphenyl phosphonium bromide and a minor amount of open-ringhydroxy ketone form. In order to convert this hydroxy ketone form of thephosphonium bromide to the tetrahydropyran form, the material is treatedwith ml. of 1 percent methanolic hydrogen bromide for 3 hours at roomtemperature. An ethereal solution of diazomethane is then added todecompose hydrobromic acid and the reaction mixture is then evaporatedto dryness in vacuo to yield 2-methox- 3 y-6-methyltetrahydropyran-Z-butyl triphenyl phosphonium bromide as a foam. I.R.?\:E and 14.4511" EXAMPLE 10 l-( 3 ,5-Dimethoxy-6-Carboxyphenyl lO-l-lydroxy- 1 -Un- 3 5 decen-6-One (X)-(Seco Acid From ZearalenoneDiemthyl Ether) A 2.35 molar solution of methylsulfinyl carbanion indimethylsulfoxide is prepared in known manner from dimethyl 4o sulfoxideand sodium hydride.

40.1 ml. of this 2.35 molar solution of methyl-sulfinyl carbanion ofdiemthyl sulfoxide is added to a stirred solution of 4.972 g. (0.00942mole) of 2-methoxy-6-methyl tetrahydropyran-Z-butyl triphenylphosphonium bromide in 12 ml. of dry diemthyl sulfoxide. The resultingdeep red solution is stirred for 10 minutes under N at room temperature,during which time the corresponding phosphorane is formed.

A solution of sodium-2-formyl-4,6-dimethoxy-benzoate is prepared byadding 4.0] ml. of the 2.35 molar solution of methyl sulfmyl carbanionin diemthyl sulfoxide to 1.98 g. of 2formyl-4,6-dimethoxy benzoic acidin 10 ml. of dimethyl sulfoxide. This latter solution of benzoate saltis added with stirring to the above solution of phosphorane. Theresulting reaction mixture is stirred at room temperature for 15 hours.It is then diluted with about an equal volume of water and extractedwith ether. The ether layer is removed; the aqueous alkaline layer ismade just acidic with dilute aqueous hydrochloric acid and extractedwith fresh ether. This latter ethereal extract is extracted with 5percent aqueous sodium bicarbonate and the resulting aqueous alkalinesolution made just acidic with dilute hydrochloric acid-This aqueousacidic solution is extracted with ether. This latter ether extract iswashed with a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate and finally evaporated to dryness in vacuo toafford a residue consisting of 1.9 g. of l-(3,5-dimethoxy-6-carboxyphenyl)- l O-hydroxy-o l flingQQfiflfi-QPEALRJACUIZCI 2.8-4.3, 5.81, 5,88, 6.24 and 10:31 As deter- EXAMPLE 1 l d,l-Zearalenone Dimethyl Ether (XI) 20 ml. of trifluoroacetic anhydride isadded dropwiseover l "hour to a stirred cold (10 C.) solution of 10.0 g.of racemic seco acid, i.e.,l-(3,5-dimethoxy-6-caroxyphenyl)-lO-hydroxy-l-undecen-6-one in 2,800 ml.of benzene. The addition is carried out in a nitrogen atmosphere. Thecooling bath is then removed and the mixture stirred for an additionalhour. It is then cooled to 10 C. and 5 percent aqueous sodium hydroxideis added (about 200 ml.) with stirring until the mixture is basic. Thelayers are separated, the aqueous layer is extracted twice with benzene,and the combined benzene layer and extracts washed twice with water,once with saturated sodium chloride solution, dried over magnesiumsulfate and concentrated to dryness under vacuum. The residue isdissolved in chloroform and chromatographed on about 150 g. of silicagel H. The column is eluted with chloroform containing 4percent acetone.The fractions containing the d,l-zearalenone dimethyl ether (asdetermined by thin-layer chromotography) are combined and concentratedto dryness in vacuo. The residue thus obtained is crystallized from 9:1ether-acetone to give pure d, l-zearalenone dimethyl ether, m.p. l24l 26C.

EXAMPLE l2 d,l-Zearalenone (Xll) A. To a stirred solution of 120 mg. ofd,l-zearalenone dimethyl ether in 1.2 ml. of methylene chloride undernitrogen at 0 C. there is added a cooled (0 C.) solution of 0.5 ml. ofboron tribromide in 0.8 ml. of methylene chloride. The cooling bath isremoved and after 5 minutes the reaction mixture is concentrated todryness under water pump vacuum (bath 0 temperature 30 C.). Theresulting solid residue is triturated with 5 ml. of water and theprecipitate filtered, washed with water and dried under vacuum to give121 mg. of crude d,lzearalenone. The product is purified by preparativethin-layer chromatography of silica gel G coated glass plates usingchloroform-5 percent acetonitrile as the developing solvent. The productis removed from the glass plates, dissolved in a minimum volume ofacetone, and hexane added to the acetone solution until crystallizationbegins. The crystalline product is filtered off and dried to give pured,l-zearalenone, m.p. l87-l89C.

B. A mixture of 500mg. of d,l-zearalenone dimethyl ether and 5.0g. ofpyridine hydrochloride is held under nitrogen for lhour at l-l85 C. Themixture is then cooled, dilute aqueous hydrochloric acid added to it,and the whole extracted with 2 ml. of methylene chloride. The methylenechloride extracts are combined, washed with saturated aqueous sodiumchloride, dried over sodium sulfate and finally concentrated in vacuo todryness. The residue is purified by thin-layer chromatography andcrystallization from acetonehexane according to the procedure set forthin part A above.

EXAMPLE 13 d, l -Zearalenone-4-Monomethyl Ether (Xlll) To a stirredsolution of 480 mg. of d,l-Zearalenone dimethyl ether in 5 ml. ofmethylene chloride under nitrogen at 0 C. there is added a cooled (0 C.)solution of 2 ml. of boron tribromide in 2 ml. of methylene chloride.The reaction mixture is immediately poured into 50 ml. of crushed icewith stirring. The mixture is made basic with potassium bicarbonate andextracted with methylene chloride. The latter extract is washed withsaturated aqueous sodium chloride, dried over magnesium sulfate andtaken to dryness under vacuum. Thin-layer chromatography (silica-gelG-chloroform-Spercent acetonitrile) shows the presence of a minor amountof d,l- Zearalenone and a major amount of d,l-zearalenone-4- monomethylether. the monomethyl ether is isolated and purified by preparative thinlayer chromotography (as described in example 12) to affordsubstantially pure material.

EXAMPLE 14 l-( 3 ,5-Dimethoxy-6-Carboxyphenyl 1 O-Hydroxy- 1-Undecen-6-One A. To a stirred solution of 10 g. of zearalenone dimethylether [2-( l0-hydroxy-6-oxol -undecenyl)-4,6-dimethoxy benzoic acidu-lactone (11)] in 100 ml. of dime thylsulfoxide maintained undernitrogen there is added dropwise 60 ml. of 20 percent aqueous sodiumhydroxide. During the addition the solution turns red and the flask isheated until the mixture refluxes gently. (Internal temperature about120 C.). After 2 hours of gentle reflux the solution is cooled to 10l5C. and added with stirring to 300 ml. of cold water l-l5 C.). Themixture is made acidic with 2.5N hydrochloric acid and extracted fourtimes with chloroform. The combined chloroform extracts are in turnextracted with dilute aqueous potassium bicarbonate. The latter aqueousextract is washed once with chloroform and acidified with dilutehydrochloric acid. The mixture is extracted with chloroform, the latterchloroform extracted washed with saturated aqueous sodium chloride,dried over sodium sulfate and concentrated to dryness under vacuum. d, l3 ,5-dimethoxy-6-carboxyphenyl)- l O-hydroxylundecen-6-one is obtainedas a pale yellow viscous oil. l.R.

' ACHC'a-lj, 5,81, 5,88, 6.24 and 10.31

B. Diazomethane is generated by the procedure of DeBoer [Rec. Trav.Chem. 73 229( 1954)] and under a gentle nitrogen stream excessdiazomethane is passed into a solution of 4.0 g. of d, l l3,5-dimethoxy-6 -carboxyphenyl)-10-hydroxy-l-undecen -6-one in 50 ml. oftetrahydrofuran. After minutes excess diazomethane and solvent areremoved under vacuum to give a residue ofd,l-1-(3,5-dimethoxy-6-carbomethoxyphenyl) l O-hydroxyl -undecen-6-one.

Any departure from the above description which conforms to the presentinvention is intended to be included within the scope of the claims.

We claim:

1. A compound having the structural formula:

wherein R and R,represent lower alkyl or benzyl, R represents hydrogenand alkali metal salts thereof.

2. The compound of claim 1 wherein R and R, are methyl, and R ishydrogen.

3. The process for preparing the compound of claim 1 wherein R ishydrogen that comprises treating zearalenone diakyl ether with aqueousalkali metal hydroxide in the presence of dimethylsulfoxide.

4. The process for preparing the compound of claim 1 wherein R and R areloweralkyl or benzyl and R is hydrogen that comprises treating a2-loweralkoxy-6-methyltetrahydropyran-Z-butyl triaryl phosphonium halidewith methyl sulfinyl carbanion to form the corresponding phosphorane andreacting said phosphorane with an alkali metal salt of 2-formyl-4-OR,-6-OR -benzoic acid, where R and R are as defined above.

5. The process for preparing the compound of claim 2 that comprisestreating 2-methoxy-6-methyl-tetrahdyropyran-2- butyl triphenylphosphonium bromide with methyl sulfinyl carbanion to from thecorresponding phosphorane and reacting said phosphorane with sodium2-formyl-4,6-dimethoxy benzoate.

2. The compound of claim 1 wherein R and R1 are methyl, and R2 ishydrogen.
 3. The process for preparing the compound of claim 1 whereinR2is hydrogen that comprises treating zearalenone dialkyl ether withaqueous alkali metal hydroxide in the presence of dimethylsulfoxide. 4.The process for preparing the compound of claim 1 wherein R and R1 areloweralkyl or benzyl and R2 is hydrogen that comprises treating a2-loweralkoxy-6-methyl-tetrahydropyran-2-butyl triaryl phosphoniumhalide with methyl sulfinyl carbanion to form the correspondingphosphorane and reacting said phosphorane with an alkali metal salt of2-formyl-4-OR1-6-OR-benzoic acid, where R and R1 are as defined above.5. The process for preparing the compound of claim 2 that comprisestreating 2-methoxy-6-methyl-tetrahdyropyran-2-butyl triphenylphosphonium bromide with methyl sulfinyl carbanion to form thecorresponding phosphorane and reacting said phosphorane with sodium2-formyl-4,6-dimethoxy benzoate.